EP0994849B1 - Method for production of 2,4,5-trifluorobenzonitrile - Google Patents

Description

The invention relates to a process for producing 2,4,5-trifluoro-benzonitrile, which is used as a starting material for active ingredients in the field of medicine and agriculture place.

It is known that 2,4,5-trifluoro-benzonitrile is obtained when 1-bromo-2,4,5-trifluoro-benzene with copper (I) cyanide and N-methyl-pyrrolidone in a sealed The reaction vessel is heated to temperatures between 170 ° C and 190 ° C for several hours (see EP-A-191 185). However, one obtains this method of synthesis a heavily contaminated product that is only sufficient after column chromatography Purity can be isolated.

According to a somewhat modified procedure, 1-bromo-2,4,5-trifluoro-benzene can be used Copper (I) cyanide even when using N, N-dimethylformamide as a solvent and heated under reflux for a longer time in 2,4,5-trifluoro-benzonitrile (see J. Med. Chem. 31 (1988), 983-991). The isolation of pure 2,4,5-trifluoro-benzonitrile is not described in this publication.

It is also known that 2-chloro-3,4,5-trifluorobenzonitrile can be obtained if the corresponding amine is first diazotized with sodium nitrite / hydrochloric acid and the product obtained subsequently with equimolar amounts of copper sulfate and an excess of potassium cyanide in aqueous ammonia to the nitrile (see EP-A-682 008).

Next is the reaction of 2,4-dichloro-5-fluoro-benzonitrile with potassium fluoride, if appropriate in the presence of reaction aids, e.g. Cesium fluoride and Octadecyl-trimethylammonium chloride, in the presence of diluents such as e.g. Dimethyl sulfoxide, tetramethylene sulfone (sulfolane) and toluene, at temperatures above 150 ° C (see EP-A-431 373, EP-A-433 124, EP-A-497 239, EP-A-635 486). However, 2,4,5-trifluorobenzonitrile is usually used in addition to this other products obtained only in low or moderate yields. Only at Use of larger amounts of phase transfer catalysts, in particular of tetraalkylphosphonium halides is said to be 2,4,5-trifluoro-benzonitrile in higher Yields are obtained (see EP-A-557 949).

It is also known that 2,4,5-trifluoro-benzonitrile mixed with other fluorination products also by reacting 2,4-difluoro-benzonitrile with elemental Fluorine can be obtained at low temperatures (see EP-A-566 268).

The synthesis of some trihalobenzonitriles - but not of 2,4,5-trifluorobenzonitrile - is also starting from corresponding trihalogen anilines via the diazonium salts and their reaction with metal cyanides have been described (for this "Sandmeyer method" see GB-A-951 770, Coll. Czech. Chem. Com. 42 (1977), 2001 to 2017). However, the quality or yield of the products thus obtained are not satisfactory.

The object of the present invention is to provide a method whereby 2,4,5-Trifluorobenzonitrile in high purity and with high yields of 2,4,5-trifluoro-aniline can be produced.

worin 2,4,5-Trifluor-anilin der Formel (II)

in einem ersten Schritt A) mit einem Nitrosierungsmittel in Gegenwart eines Verdünnungsmittels umgesetzt wird
und worin in einem zweiten Schritt B) das im Schritt A) erhaltene Reaktionsprodukt mit einem Alkalimetallcyanid in Gegenwart einer Übergangsmetallverbindung, wobei die Übergangsmetallverbindung zwischen 0,01 und 0,5 Mol bezogen auf 1 Mol des im ersten Schritt eingesetzten 2,4,5-Trifluor-anilins eingesetzt wird, eines Säureakzeptors und eines Verdünnungsmittels umgesetzt wird.The object is achieved by a process for the preparation of 2,4,5-trifluoro-benzonitrile of the formula (I)

wherein 2,4,5-trifluoro-aniline of the formula (II)

in a first step A) with a nitrosating agent in the presence of a diluent
and in a second step B) the reaction product obtained in step A) with an alkali metal cyanide in the presence of a transition metal compound, the transition metal compound being between 0.01 and 0.5 mol based on 1 mol of the 2,4,5- Trifluoro-aniline is used, an acid acceptor and a diluent is implemented.

Surprisingly, 2,4,5-trifluoro-benzonitrile can be used in the process according to the invention can be obtained with high yield and in high purity.

The reaction temperatures can be carried out when carrying out the process according to the invention Process can be varied over a wide range. Generally you work in the first step at temperatures between -20 ° C and + 30 ° C, preferably between -10 ° C and + 20 ° C, in the second step generally at temperatures between -10 ° C and + 40 ° C, preferably between 0 ° C and + 30 ° C.

The two steps of the process according to the invention are generally described in Normal pressure carried out. However, it is also possible to use the method according to the invention under increased or reduced pressure - generally between 0.1 bar and 10 bar.

The starting compound 2,4,5-trifluoro-aniline is known and easy to prepare (see GB-A-11 31 501, EP-A-415 585).

The first step of the method according to the invention is carried out using a Nitrosating agent carried out. The usual ones are used for production suitable nitrosating agents from diazonium salts. As examples of this are mentioned:

Alkali metal nitrites, e.g. Sodium and potassium nitrite (in the presence of an acid, such as. Sulfuric acid, methanesulfonic acid, formic acid or acetic acid), alkyl nitrites, such as. Methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl-, n-, i-, s- or t-pentyl nitrite, also nitrosyl sulfuric acid.

Nitrosylsulfuric acid is used as a nitrosating agent when carrying out the first Step of the method according to the invention is particularly preferred.

The second step of the method according to the invention is carried out using a Alkali metal cyanide performed. Preferred alkali metal cyanides are Sodium cyanide or potassium cyanide used. In addition, a transition metal compound, preferably a copper compound, e.g. Copper cyanide or copper sulfate used. Surprisingly, the transition metal compound can be wide below the stoichiometric amount, i.e. thus used in a catalytic amount become.

The second step of the method according to the invention is still in the presence performed an acid acceptor. In general, the acid acceptors are usual inorganic or organic bases or acid binders into consideration. These preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, bicarbonates, hydrides, hydroxides or alkanolates, such as, for example Sodium, potassium or calcium acetate, lithium, sodium, potassium or Calcium amide, sodium, potassium or calcium carbonate, sodium, potassium or Calcium hydrogen carbonate, lithium, sodium, potassium or calcium hydride, Lithium, sodium, potassium or calcium hydroxide, sodium or potassium methoxide, -ethanolate, -n- or -i-propanolate, -n-, -i-, -s- or -t-butanolate; continue too basic organic nitrogen compounds, such as trimethylamine, triethylamine, Tripropylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylcyclohexylamine, Dicyclohexylamine, ethyl-dicyclohexylamine, N, N-dimethyl-aniline, N, N-dimethyl-benzylamine, pyridine, 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethyl-pyridine, 5-ethyl-2-methyl-pyridine, 4-dimethylamino-pyridine, N-methyl-piperidine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), or 1.8 diazabicyclo [5,4,0] -undec-7-ene (DBU).

Alkali metal or alkaline earth metal carbonates or hydrogen carbonates are preferably such as. Sodium or potassium (hydrogen) carbonate used.

The process according to the invention is carried out in the presence of a diluent carried out. As a diluent for carrying out the method according to the invention inert organic solvents are particularly suitable. This includes in particular aliphatic, alicyclic or aromatic, optionally halogenated Hydrocarbons, such as gasoline, benzene, toluene, xylene, Chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, Carbon tetrachloride; Ethers, such as diethyl ether, diisopropyl ether, dioxane, Tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; Ketones, such as acetone, Butanone or methyl isobutyl ketone; Carboxylic acid, e.g. formic acid, Acetic acid or propionic acid; Nitriles such as acetonitrile, propionitrile or butyronitrile; Amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methyl-pyrrolidone or hexamethylphosphoric triamide; Esters such as methyl acetate or ethyl acetate, sulfoxides, such as dimethyl sulfoxide, alcohols, such as methanol, ethanol, n- or i-propanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, Diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, their mixtures with water or pure water.

Carboxylic acids are used as diluents when performing the first Step of the method according to the invention is particularly preferred. During execution the second step of the method according to the invention is preferred Water used as another solvent.

To carry out the first step of the method according to the invention, to 1 mol of 2,4,5-trifluoro-aniline of the formula (II) generally between 0.9 and 1.2 Mol, preferably between 1.0 and 1.1 mol of a nitrosating agent.

In a preferred embodiment of the first step of the invention The process is the 2,4,5-trifluoro-aniline of the formula (II) in a suitable diluent submitted and the nitrosating agent is slow with stirring metered. The reaction mixture is then further stirred until the reaction is practically complete according to the first step.

To carry out the second step of the method according to the invention based on 1 mol of the 2,4,5-trifluoro-aniline used in the first step Formula (II) generally between 1 and 10 mol, preferably between 2 and 8 Moles of an alkali metal cyanide and between 0.01 and 0.5 moles, preferably between 0.05 and 0.2 moles of a transition metal compound.

In a preferred embodiment of the second step of the invention The process is obtained under the first step under Stir to an aqueous solution of alkali metal cyanide and transition metal compound given, with the simultaneous addition of an acid acceptor the pH is kept approximately in the neutral range. The reaction mixture is then stirring continued until the reaction is practically complete.

The reaction product obtained in the first step is preferably used before the reaction not isolated in the second step.

The work-up and isolation of the reaction product of formula (I) can done in the usual way. For example, practically not with a water miscible organic solvents, e.g. Ethyl acetate, shaken and from the organic extraction solution then the solvent under reduced Pressure carefully distilled off, leaving the product of formula (I) as a residue remains.

The compound 2,4,5-trifluoro-benzonitrile to be produced by the process according to the invention of the formula (I) can be used as an intermediate for the preparation of active substances used in the field of medicine and agriculture (see EP-A-191 185, EP-A-597 360, EP-A-617 026, EP-A-654 468).

Preparation Examples: example 1

4.4 g (30 mmol) of 2,4,5-trifluoro-aniline are dissolved in 25 ml of acetic acid ("glacial acetic acid") and chilled with an ice bath. Then 4.5 g (31.5 mmol) of nitrosylsulfuric acid with stirring added and the reaction mixture is after removing the Ice bath stirred for another hour (first step).

The diazonium salt solution thus obtained is then cooled to a temperature of 5 ° C. with stirring Solution of 7.8 g (160 mmol) sodium cyanide and 0.3 g (3 mmol) copper (I) cyanide placed in 40 ml of water. By simultaneously adding approx. 80 ml of one 25% aqueous solution of sodium carbonate, the pH is approximated in Kept neutral. Then the reaction mixture is about 15 minutes stirred and then extracted twice with 100 ml of ethyl acetate. Of The combined organic extraction solutions, the solvent in a water jet vacuum carefully distilled off.

4.1 g (92% product according to gas chromatographic analysis, i.e. 80% of theory) 2,4,5-trifluoro-benzonitrile as an oily residue.

Claims (12)

1. Process for preparing 2,3,5-trifluoro-benzonitrile, characterized by the following steps:

   A) reaction of 2,4,5-trifluoro-aniline with a nitrosating agent in the presence of a diluent;

   B) reaction of the reaction product obtained in step A) with an alkali metal cyanide in the presence of a transition metal compound which is employed in an amount between 0.01 and 0.5 mol per mole of the 2,4,5-trifluoro-aniline employed in the first step, an acid acceptor and a diluent.
2. Process according to Claim 1, characterized in that, in step B), the reaction product obtained in step A) is added to an aqueous solution of alkali metal cyanide and transition metal compound with simultaneous metered addition of an acid acceptor such that the pH of the aqueous solution is maintained in the neutral range.
3. Process according to Claim 1 or 2, characterized in that the reaction in step B) is carried out in the presence of between 0.05 and 0.2 mol of a transition metal compound per mole of the 2,4,5-trifluoro-aniline employed in step A).
4. Process according to any of Claims 1 to 3, characterized in that the reaction in step A) is carried out at a temperature between -20°C and +30°C, preferably between -10°C and +20°C, and the reaction in step B) is carried out at a temperature between -10°C and +40°C, preferably between 0°C and +30°C.
5. Process according to any of Claims 1 to 4, characterized in that the nitrosating agents used are alkali metal nitrites, alkyl nitrites and/or nitrosylsulphuric acid.
6. Process according to Claim 5, characterized in that the nitrosating agent used is nitrosylsulphuric acid.
7. Process according to any of Claims 1 to 6, characterized in that the alkali metal cyanide used is sodium cyanide and/or potassium cyanide.
8. Process according to any of Claims 1 to 7, characterized in that the transition metal compound used is a copper compound, preferably copper cyanide and/or copper sulphate.
9. Process according to any of Claims 1 to 8, characterized in that the acid acceptors used are alkali metal carbonates and/or alkaline earth metal carbonates and/or alkali metal bicarbonates and/or alkaline earth metal bicarbonates, preferably sodium (bi)carbonate and/or potassium (bi)carbonate.
10. Process according to any of Claims 1 to 9, characterized in that the diluent used comprises one or more inert organic solvents.
11. Process according to Claim 10, characterized in that the diluents used in step A) are carboxylic acids and in step B) are additionally water.
12. Process according to any of Claims 1 to 11, characterized in that the reaction product obtained in step A) is not isolated prior to the reaction in step B).